This proposal includes: one clinical Project (Project 2: PI: Dr. Fabry) that builds on the pioneering work of the PI in the last cycle on the development of BOLD-MRI and now near infrared spectroscopy (NIRS) to measure oxygenation perfusion and blood volume in sickle cell patients and novel sickle transgenic mice. The objective is to determine if these state-of-the-art technologies can help in the evaluation of sickle damage to brain, kidney and muscle. In addition, there are three Translational Research projects that aim at finding potentially helpful therapeutic interventions in SCD by the pre-clinical development of several basic research strategies. They are: Project 1 (PI: Dr. Acharya) who is interested in generating a globin chain that has more polymerization inhibitory potential than the paradigmatic HbF, based on the pioneering finding, in the previous cycle, that pig-alpha-chain completely neutralizes human beta5-polymerization. The follow-up is to define the minimum number of pig-alpha-chain sequences that are sufficient to confer the desired properties on the human alpha-globin chain. In the process, we will learn about the quinary structure of sickle polymer as well as the refinement of semisynthesis. Project 3 (PI: Dr. Kaul). also builds on work done in the previous cycle, but the present proposal aims at a quantum leap of knowledge as it pertains to: testing the hypotheses that a heterogenous array of red cell integrins and vWF, P-selectin, laminin, and NO are involved in sickle adhesion, and testing the hypothesis that alphaVBeta3 anionic polysaccharides, and hydroxyurea, can be useful in blocking sickle cell adhesion. Project 4 (PI; Dr. Nagel), builds on a long interest in the multigene involvement in the sickle phenotype. This project aims at defining, by state-of-the art microarray technology, the genes responsible for the pleiotropic effects in sickle cell anemia, as well as which of these have epistatic (modifier) capability to define severity risk and to explore potential epigenetic effects in Beta-gene cluster haplotypes linked to the sickle gene. The projects are supported by an Administrative Core, Transgenic Core (in the forefront of developing sickle animal models), by a micro-CHIP Core (supposed also by our in-house Microarray Facility), a strong Clinical and Patient Services Core, that has pioneered the Day Hospital concept into reality, with the purpose of treating sickle cell anemia patients with uncomplicated painful crises in a way that greatly improves their rate of recovery, their hospitalization rates, and that also favorably affects the in house hospitalization length of stay. This proposal is complemented by two above-the-cap Clinical Project Proposals, both based on last cycle accomplishments.